Antigens initiate immune responses and activate the two largest populations of lymphocytes: T cells and B cells. After encountering antigen, T cells proliferate and differentiate into effector cells, while B cells proliferate and differentiate into antibody-secreting plasma cells. Proliferation and differentiation of lymphocytes are regulated by extracellular proteins. Some of these proteins are called cytokines, which are small proteins (<30 kDa) secreted by lymphocytes and other cell types.
Interleukin-21 (IL-21) is a recently discovered cytokine, which is closely related to IL-2, IL4 and IL-15 (Parrish-Novak et al. (2000) Nature 408:57-63). Human IL-21 has a molecular weight of about 15 kDa, consists of 131 amino acids, and shares about 57% identity with mouse IL-21. IL-21 is produced primarily by activated CD4+ T cells.
IL-21 receptor (IL-21R) is a transmembrane, IL-21-binding protein that belongs to the class I cytokine receptor family. Both human and mouse IL-21R have been described in WO 01/85792, herein incorporated by reference. The predicted size of human IL-21R is about 529 amino acids. IL-21R shows high sequence homology to IL-2 receptor β chain and IL-4 receptor α chain (Ozaki et al. (2000) Proc. Natl. Acad. Sci. USA 97:11439-11444). The human and mouse IL-21R amino acid sequences share about 62% identity. Upon ligand binding, IL-21R associates with the common gamma cytokine receptor chain (γc) that is shared by receptors for IL-2, IL-3, IL-4, IL-7,IL-9, IL-13 and IL-15 (Ozaki et al. (2000) supra; Asao et al. (2001) J. Immunol. 167:1-5).
IL-21R is expressed primarily in lymphoid tissues, such as B cells, T cells, and natural killer (NK) cells. The widespread lymphoid distribution of IL-21R suggests that IL-21 may play a role in immune regulation. Indeed, in vitro studies have shown that IL-21 significantly modulates the function of B cells, CD4+ and CD8+ T cells, and NK cells (Parrish-Novak et al. (2000) supra; Kasaian, M. T. et al. (2002) Immunity. 16:559-569). IL-21 and IL-21R have also been shown to be important for modulating the activity of macrophages, and synovial cells. For example, IL-21 augments the proliferation of B cells stimulated with anti-CD40 antibody, and suppresses the proliferation of B cells stimulated with anti-IgM and IL-4. IL-21 augments the proliferation and cytolytic activity of T cells and human NK cells. IL-21 also mediates the expression of cytokines, chemokines, or combination thereof, secreted by T cells, NK cells, macrophages, and synovial cells. Because of the dependence of B cells, T cells, NK cells, macrophages, and synovial cells on IL-21, altering IL-21 binding to IL-21R may affect certain immune responses. Such a manipulation provides a means for treating immune system disorders, such as autoimmune disease disorders, inflammatory disorders, allergies, transplant rejection, cancer, immune deficiency, and other disorders.